Inherited diseases are often uncommon in themselves, but a good source of insight for understanding common, complex diseases. We study the causes and develop better treatments for inherited disorders of the immune system. These include immunodeficiencies, in which gene defects impair the ability of the immune system to fight infections and also disorders of immune cell regulation, in which autoimmunity may be seen. Current areas of investigation include autoimmune lymphoproliferative syndrome (ALPS), severe combined immunodeficiency, mucocutaneous candidiasis, hyper-IgE syndrome (also known as Job syndrome after the biblical character who was stricken with boils), and other conditions. Patients with ALPS have large lymph nodes and spleens, increased numbers of a rare type of lymphocyte called CD4-/CD8- T cells, or double-negative T cells, and defects in programmed cell death, or apoptosis of their lymphocytes. We found that most patients with ALPS have inherited mutations in the apoptosis mediator Fas. Their lymphocytes do not die when they should. Instead, they accumulate and can attack the body's own tissues. Autoimmune diseases of the red blood cells, platelets and white blood cells are common in ALPS. We found some affected members of ALPS families who are more severely affected than others. Modifying genes that influence severity of ALPS are being sought. Some patients with no mutation in the Fas gene have defects in related genes such as caspase-10. Hyper-IgE syndrome is an enigmatic, rare condition characterized by recurrent skin infections, eczema, extreme elevations of serum IgE, and pneumonia with formation of lung cysts. The specific immune defect has not been discovered; therefore we have undertaken genetic studies to map the disease. We have also mapped dominant mucocutaneous candidiasis to human chromosome 2p and we are evaluating candidate genes. Mouse models of immune deficiency are also under study, as they are likely to advance our understanding of human immune disorders. A new form of mouse SCID has been mapped in the mouse and candidate disease genes are being tested. Part of this project involves developing and implementing sophisticated new tests of lymphocyte function. Beyond just counting lymphocytes and inducing cell activation in bulk cultures, it is important to define the range of cells that are capable of responding to infections. We have initiated new tests of T-cell excision circles (TRECs) as an indicator of newly formed T cells and spectratyping by PCR to examine the diversity of lymphocyte receptors. In addition, population screening for immune disorders is desirable to diagnose these conditions before serious or lethal infections occur. We are piloting newborn screening protocols for this application.